tbuckley/cabot-search huggingface dataset:
Efficacy of Cooling Centers for Mitigating Physiological Strain in Older Adults during Daylong Heat Exposure: A Laboratory-Based Heat Wave Simulation
Authors: Robert D. Meade, Sean R. Notley, Ashley P. Akerman, James J. McCormick, Kelli E. King, Ronald J. Sigal, Glen P. Kenny
Journal: Environmental Health Perspectives (2023)

Background: Health agencies, including the U.S. Centers for Disease Control and Prevention and the World Health Organization, recommend that heat-vulnerable older adults without home air-conditioning should visit cooling centers or other air-conditioned locations (e.g., a shopping mall) during heat waves. However, experimental evidence supporting the effectiveness of brief air-conditioning is lacking. Objective: We evaluated whether brief exposure to an air-conditioned environment, as experienced in a cooling center, was effective for limiting physiological strain in older adults during a daylong laboratory-based heat wave simulation. Methods: Forty adults 64–79 years of age underwent a 9-h simulated heat wave (heat index: 37°C) with (cooling group, n=20) or without (control group, n=20) a cooling intervention consisting of 2-h rest in an air-conditioned room (∼23°C, hours 5–6). Core and skin temperatures, whole-body heat exchange and storage, cardiovascular function, and circulating markers of acute inflammation were assessed. Results: Core temperature was 0.8°C (95% CI: 0.6, 0.9) lower in the cooling group compared with the control group at the end of the cooling intervention (p&lt;0.001; hour 6), and it remained 0.3°C (95% CI: 0.2, 0.4) lower an hour after returning to the heat (p&lt;0.001; hour 7). Despite this, core temperatures in each group were statistically equivalent at hours 8 and 9, within ±0.3°C (p≤0.005). Cooling also acutely reduced demand on the heart and improved indices of cardiovascular autonomic function (p≤0.021); however, these outcomes were not different between groups at the end of exposure (p≥0.58). Discussion: Brief air-conditioning exposure during a simulated heat wave caused a robust but transient reduction in core temperature and cardiovascular strain. These findings provide important experimental support for national and international guidance that cooling centers are effective for limiting physiological strain during heat waves. However, they also show that the physiological impacts of brief cooling are temporary, a factor that has not been considered in guidance issued by health agencies. https://doi.org/10.1289/EHP11651
Adolescent exposure to low-dose THC disrupts energy balance and adipose organ homeostasis in adulthood
Authors: Lin Lin, Kwang-Mook Jung, Hye-Lim Lee, Johnny Le, Georgia Colleluori, Courtney Wood, Francesca Palese, Erica Squire, Jade Ramirez, Shiqi Su, Alexa Torrens, Yannick Fotio, Lingyi Tang, Clinton Yu, Qin Yang, Lan Huang, Nicholas DiPatrizio, Cholsoon Jang, Saverio Cinti, Daniele Piomelli
Journal: Cell Metabolism (2023)

One of cannabis' most iconic effects is the stimulation of hedonic high-calorie eating-the "munchies"-yet habitual cannabis users are, on average, leaner than non-users. We asked whether this phenotype might result from lasting changes in energy balance established during adolescence, when use of the drug often begins. We found that daily low-dose administration of cannabis' intoxicating constituent, Δ
Macrophage–endothelial cell crosstalk orchestrates neutrophil recruitment in inflamed mucosa
Authors: Xingsheng Ren, Laura D. Manzanares, Enzo B. Piccolo, Jessica M. Urbanczyk, David P. Sullivan, Lenore K. Yalom, Triet M. Bui, Connor Lantz, Hinda Najem, Parambir S. Dulai, Amy B. Heimberger, Edward B. Thorp, Ronen Sumagin
Journal: Journal of Clinical Investigation (2023)

Neutrophil (PMN) mobilization to sites of insult is critical for host defense and requires transendothelial migration (TEM). TEM involves several well-studied sequential adhesive interactions with vascular endothelial cells (ECs); however, what initiates or terminates this process is not well-understood. Here we describe what we believe to be a new mechanism where vessel associated macrophages (VAMs) through localized interactions primed EC responses to form ICAM-1 "hot spots", to support PMN TEM. Using real-time intravital microscopy (IVM) on lipopolysaccharide (LPS)-inflamed intestines in CX3CR1-EGFP macrophage-reporter mice, complemented by whole-mount tissue imaging and flow cytometry, we found that macrophage vessel association is critical for the initiation of PMN-EC adhesive interactions, PMN TEM and subsequent accumulation in the intestinal mucosa. Anti-colony stimulating factor 1 receptor (CSF1R) antibody-mediated macrophage depletion in the lamina propria and at the vessel wall resulted in elimination of ICAM-1 hot spots impeding PMN-EC interactions and TEM. Mechanistically, the use of human clinical specimens, TNFα knockout macrophage chimeras, TNFα/TNF receptor (TNFR) neutralization and multi-cellular macrophage-EC-PMN cocultures revealed that macrophage-derived TNFα and EC TNFR2 axis mediated this regulatory mechanism and was required for PMN TEM. As such, our findings identified clinically relevant mechanism by which macrophages regulate PMN trafficking in inflamed mucosa.
Causes of stillbirth and death among children younger than 5 years in eastern Hararghe, Ethiopia: a population-based post-mortem study
Authors: Lola Madrid, Addisu Alemu, Anna C Seale, Joe Oundo, Tseyon Tesfaye, Dadi Marami, Hiwot Yigzaw, Alexander Ibrahim, Ketema Degefa, Tadesse Dufera, Zelalem Teklemariam, Tadesse Gure, Haleluya Leulseged, Stefanie Wittmann, Mahlet Abayneh, Surafel Fentaw, Fikremelekot Temesgen, Melisachew M Yeshi, Mehret Dubale, Zerihun Girma, Caroline Ackley, Berhanu Damisse, Markus Breines, Stian M S Orlien, Dianna M Blau, Robert F Breiman, Ebba Abate, Yadeta Dessie, Nega Assefa, J Anthony G Scott, Merga Deresa, Gezahegn Mengesha, Tigistu Samuel, Eyoel Taye, Mohammed Aliyi, Gurmu Feyissa, Yenenesh Tilahun, Getahun Wakwaya, Simegn Tadesse, Kidish Asnake, Mariamcher Ayalew, Azeb Kidane, Emmanuel Azore, Mussie Berhanu, Mulu Berihun, Mersan Deresa, Nardos Assegid, Shirine Voller, Mahlet Mekonnen, Andualem Alemaheyu, Nana Sarkodie-Mensah, Beth Morrison, Boniface Jibendi, Asnake Worku, Alemenesh Mirkuzie, Fentabil Getnet
Journal: The Lancet Global Health (2023)

Child mortality is high in Ethiopia, but reliable data on the causes of death are scarce. We aimed to gather data for the contributory causes of stillbirth and child deaths in eastern Ethiopia.
Purpurolide C-based microneedle promotes macrophage-mediated diabetic wound healing via inhibiting TLR4-MD2 dimerization and MYD88 phosphorylation
Authors: Yitong Liu, Guiyang Xia, Yingyi Chen, Huan Xia, Junji Xu, Lijia Guo, Sheng Lin, Yi Liu
Journal: Acta Pharmaceutica Sinica B (2023)

Delayed wound healing in diabetes is a global challenge, and the development of related drugs is a clinical problem to be solved. In this study, purpurolide C (PC), a small-molecule secondary metabolite of the endophytic fungus Penicillium purpurogenum, was found to promote diabetic wound healing. To investigate the key regulation targets of PC, in vitro RNA-seq, molecular docking calculations, TLR4-MD2 dimerization SDS-PAGE detection, and surface plasmon resonance (SPR) were performed, indicating that PC inhibited inflammatory macrophage activation by inhibiting both TLR4-MD2 dimerization and MYD88 phosphorylation. Tlr4 knockout in vivo attenuated the promotion effect of PC on wound healing. Furthermore, a delivery system consisting of macrophage liposome and GelMA-based microneedle patches combined with PC (PC@MLIP MN) was developed, which overcame the poor water solubility and weak skin permeability of PC, so that successfully punctured the skin and delivered PC to local tissues, and accurately regulated macrophage polarization in diabetic wound management. Overall, PC is an anti-inflammatory small molecule compound with a well-defined structure and dual-target regulation, and the PC@MLIP MN is a promising novel biomaterial for the management of diabetic wound.
Phase I trial of KN046, a novel bispecific antibody targeting PD-L1 and CTLA-4 in patients with advanced solid tumors
Authors: Yuxiang Ma, Jinhui Xue, Yuanyuan Zhao, Yang Zhang, Yan Huang, Yunpeng Yang, Wenfeng Fang, Ye Guo, Qun Li, Xiaoxiao Ge, Jie Sun, Bangyong Zhang, Yuhan Zhang, Jinyuan Xiao, Li Zhang, Hongyun Zhao
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background KN046 is a novel bispecific antibody targeting programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). This multicenter phase I trial investigated the safety, tolerability, pharmacokinetics (PK), and efficacy of KN046 in patients with advanced solid tumors. Methods Patients who failed standard treatment were included. KN046 was administered at doses of 1, 3, and 5 mg/kg every 2 weeks (Q2W), 5 mg/kg every 3 weeks (Q3W), and 300 mg Q3W based on the modified toxicity probability interval method in the dose-escalation phase; the recommended dose was used in the expansion phase. Primary objectives were maximum tolerated dose (MTD) and recommended phase II dose (RP2D) in escalation and preliminary efficacy in expansion. Secondary objectives included PK, pharmacodynamics, safety, and tolerability of KN046. We also explored biomarkers based on PD-L1 expression, multiplex immunofluorescence (mIF) staining, and RNAseq-derived nCounter platform. Results Totally, 100 eligible patients were enrolled, including 59 with nasopharyngeal carcinoma (NPC), 36 with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), and those with other advanced solid tumors. The most common treatment-related adverse events (TRAEs) were rash (33.0%), pruritus (31.0%), and fatigue (20.0%). Grade ≥3 TRAEs were observed in 14.0% of participants. No dose-limiting toxicity occurred in the dose-escalation phase, and the MTD was not reached. The RP2D was determined as 5 mg/kg Q2W according to the pharmacokinetic–pharmacodynamic model, the preliminary exposure–response analysis, and the overall safety profile. Among 88 efficacy-evaluable participants, the objective response rate (ORR) was 12.5%, and the median duration of response was 16.6 months. In the NPC subgroup, the ORR was 15.4%, and the median overall survival (OS) was 24.7 (95% CI 16.3 to not estimable) months. In the EGFR-mutant NSCLC subgroup, the ORR was 6.3%. mIF analysis results showed patients with high CD8 expression showed longer median OS (27.1 vs 9.2 months, p=0.02); better prognosis was observed in patients with high CD8 and PD-L1 expression. Conclusions KN046 was well tolerated and showed promising antitumor efficacy in advanced solid tumors, especially in patients with NPC. The combination of both CD8 and PD-L1 expression improved the prediction of KN046 response. Trial registration numbers NCT03733951 .
Integrated spatial transcriptome and metabolism study reveals metabolic heterogeneity in human injured brain
Authors: Ping Zheng, Ning Zhang, Dabin Ren, Cong Yu, Bin Zhao, Yisong Zhang
Journal: Cell Reports Medicine (2023)

Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased samples of the diverse cell types in the brain. With the advances of multi-omics datasets, a major challenge is to validate and integrate results into a biological understanding of spatial organization and functional orientation. Here, we generate spatial transcriptomes and metabolites from six patients with brain trauma with surgical samples. The resulting spatial marker gene, which is highly replicable across analysis methods, sequencing technologies, and modalities, is a comprehensive molecular marker of the diverse metabolic changes in human injured brains. The atlas includes an area of lipid peroxidation that resembles injured neurons in the brain. We further discover imbalanced myo-inositol and myo-inositol phosphate and related spatial markers. Our results highlight the complex transcriptomic regulation and metabolic alterations in the injured brain and will directly enable the design of reagents to target specific genes in the human brain for functional analysis.
3D Bioprinting of Neurovascular Tissue Modeling with Collagen‐Based Low‐Viscosity Composites
Authors: Sen Wang, Luge Bai, Xiaoxuan Hu, Siqi Yao, Zhiyan Hao, JiaJia Zhou, Xiao Li, Haixia Lu, Jiankang He, Ling Wang, Dichen Li
Journal: Advanced Healthcare Materials (2023)

In vitro neurovascular unit (NVU) models are valuable for investigating brain functions and developing drugs. However, it remains challenging to recapitulate the native architectural features and ultra-soft extracellular matrix (ECM) properties of the natural NVU. Cell-laden bioprinting is promising to prepare complex living tissues, but hard to balance the fidelity and cell growth. This study proposes a novel two-stage methodology for biomanufacturing functional 3D neurovascular constructs in vitro with low modulus of ECM. At the shaping stage, a low-viscosity alginate/collagen is printed through an embedded approach; at the culturing stage, the alginate is removed through targeted lysing. The low-viscosity and rapid crosslinking properties provide a printing resolution of ≈10 µm, and the lysis processing can decrease the hydrogels' modulus to ≈1 kPa and adjust the porosity of the microstructure, providing cells with an environment closing to the brain ECM. A 3D hollow coaxial neurovascular model is fabricated, in which the endothelial cells has expressed tight junction proteins and shown selective permeability, and the astrocytes outside of the endothelial layer are found to spread out with branches and directly interact with endothelial cells. The present study offers a promising modeling method for better understanding the NVU function and screening neuro-drugs.
Fit and forget: The future of dental implant therapy via nanotechnology
Authors: Karan Gulati, Divya Chopra, Necla Asli Kocak-Oztug, Elise Verron
Journal: Advanced Drug Delivery Reviews (2023)

Unlike orthopedic implants, dental implants require the orchestration of both osseointegration at the bone-implant interface and soft-tissue integration at the transmucosal region in a complex oral micro-environment with ubiquitous pathogenic bacteria. This represents a very challenging environment for early acceptance and long-term survival of dental implants, especially in compromised patient conditions, including aged, smoking and diabetic patients. Enabling advanced local therapy from the surface of titanium-based dental implants via novel nano-engineering strategies is emerging. This includes anodized nano-engineered implants eluting growth factors, antibiotics, therapeutic nanoparticles and biopolymers to achieve maximum localized therapeutic action. An important criterion is balancing bioactivity enhancement and therapy (like bactericidal efficacy) without causing cytotoxicity. Critical research gaps still need to be addressed to enable the clinical translation of these therapeutic dental implants. This review informs the latest developments, challenges and future directions in this domain to enable the successful fabrication of clinically-translatable therapeutic dental implants that would allow for long-term success, even in compromised patient conditions.
Unique Issues Facing Sexual and Gender Minorities in Cancer
Authors: NFN Scout
Journal: Cancer Discovery (2023)

Summary: There are few resources available that help providers understand unique issues sexual and gender minority (SGM) people face related to cancer screening and care. This article helps fill the gap by providing some of the top-line issues providers and policymakers should know, as assembled by one of the leading experts in this field, the executive director of the National LGBT Cancer Network. The sexual and gender minority (SGM) cancer field has matured significantly in recent years, providing greater insight into the barriers and challenges experienced by this population. Not only are risks of cancer for the population higher, but SGM people also experience low access to tailored resources and ultimately lower satisfaction with care after treatment. This article will lay out key issues related to cancer and this population, including changing demographics, no presumption of care, other access to care barriers, systematic data suppression, and then the lack of population-specific cancer research. It will also review the first step in building a more welcoming clinical practice and give resources for additional steps.
Defining Goals and Investing in Data to Improve Postpartum Health and Health Equity
Authors: Jamie R. Daw, Elizabeth A. Howell
Journal: JAMA Network Open (2023)

Ian J. Saldanha, MBBS, MPH, PhD; Gaelen P. Adam, MLIS, MPH; Ghid Kanaan, MD; Michael L. Zahradnik, MSc; Dale W. Steele, MD, MS; Kenneth K. Chen, MD; Alex F. Peahl, MD, MSc; Valery A. Danilack-Fekete, MPH, PhD; Alison M. Stuebe, MD, MSc; Ethan M. Balk, MD, MPH
Chemobrain in blood cancers: How chemotherapeutics interfere with the brain's structure and functionality, immune system, and metabolic functions
Authors: M. Skurlova, K. Holubova, L. Kleteckova, T. Kozak, H. Kubova, J. Horacek, K. Vales
Journal: Medicinal Research Reviews (2023)

Cancer treatment brings about a phenomenon not fully clarified yet, termed chemobrain. Its strong negative impact on patients' well-being makes it a trending topic in current research, interconnecting many disciplines from clinical oncology to neuroscience. Clinical and animal studies have often reported elevated concentrations of proinflammatory cytokines in various types of blood cancers. This inflammatory burst could be the background for chemotherapy-induced cognitive deficit in patients with blood cancers. Cancer environment is a dynamic interacting system. The review puts into close relationship the inflammatory dysbalance and oxidative/nitrosative stress with disruption of the blood-brain barrier (BBB). The BBB breakdown leads to neuroinflammation, followed by neurotoxicity and neurodegeneration. High levels of intracellular reactive oxygen species (ROS) induce the progression of cancer resulting in increased mutagenesis, conversion of protooncogenes to oncogenes, and inactivation of tumor suppression genes to trigger cancer cell growth. These cell alterations may change brain functionality, as well as morphology. Multidrug chemotherapy is not without consequences to healthy tissue and could even be toxic. Specific treatment impacts brain function and morphology, functions of the immune system, and metabolism in a unique mixture. In general, a chemo-drug's effects on cognition in cancer are not direct and/or in-direct, usually a combination of effects is more probable. Last but not least, chemotherapy strongly impacts the immune system and could contribute to BBB disruption. This review points out inflammation as a possible mechanism of brain damage during blood cancers and discusses chemotherapy-induced cognitive impairment.
PI*ZQ0Attikon genotype discovery in severe alpha-1 antitrypsin deficiency
Authors: S.A. Papiris, M. Veith, A. Lazaratou, M. Balduyck, C. Lombard, M. Dechomet, M.-F. Odou, E. Entrena, L. Osaba, M. Kallieri, V. Apollonatou, S. Prountzos, C. Kontopoulou, L. Kolilekas, I. Ferrarotti, J.-F. Mornex, C.-F. Vogelmeier, T. Greulich, E.D. Manali
Journal: Pulmonology (2023)
Genetic Alterations Detected by Circulating Tumor DNA in HER2-Low Metastatic Breast Cancer
Authors: Whitney L. Hensing, Lorenzo Gerratana, Katherine Clifton, Arielle J. Medford, Marko Velimirovic, Ami N. Shah, Paolo D'Amico, Carolina Reduzzi, Qiang Zhang, Charles S. Dai, Elyssa N. Denault, Nusayba A. Bagegni, Mateusz Opyrchal, Foluso O. Ademuyiwa, Ron Bose, Amir Behdad, Cynthia X. Ma, Aditya Bardia, Massimo Cristofanilli, Andrew A. Davis
Journal: Clinical Cancer Research (2023)

About 50% of breast cancers are defined as HER2-low and may benefit from HER2-directed antibody-drug conjugates. While tissue sequencing has evaluated potential differences in genomic profiles for patients with HER2-low breast cancer, genetic alterations in circulating tumor DNA (ctDNA) have not been well described.We retrospectively analyzed 749 patients with metastatic breast cancer (MBC) and ctDNA evaluation by Guardant360 from three academic medical centers. Tumors were classified as HER2-low, HER2-0 (IHC 0) or HER2-positive. Single-nucleotide variants, copy-number variants, and oncogenic pathways were compared across the spectrum of HER2 expression. Overall survival (OS) was evaluated by HER2 status and according to oncogenic pathways.Patients with HER2-low had higher rates of PIK3CA mutations [relative risk ratio (RRR), 1.57; P = 0.024] compared with HER2-0 MBC. There were no differences in ERBB2 alterations or oncogenic pathways between HER2-low and HER2-0 MBC. Patients with HER2-positive MBC had more ERBB2 alterations (RRR, 12.43; P = 0.002 for amplification; RRR, 3.22; P = 0.047 for mutations, in the hormone receptor-positive cohort), fewer ERS1 mutations (RRR, 0.458; P = 0.029), and fewer ER pathway alterations (RRR, 0.321; P < 0.001). There was no difference in OS for HER2-low and HER2-0 MBC [HR, 1.01; 95% confidence interval (CI), 0.79-1.29], while OS was improved in HER2-positive MBC (HR, 0.32; 95% CI, 0.21-0.49; P < 0.001).We observed a higher rate of PIK3CA mutations, but no significant difference in ERBB2 alterations, oncogenic pathways, or prognosis, between patients with HER2-low and HER2-0 MBC. If validated, our findings support the conclusion that HER2-low MBC does not represent a unique biological subtype.
Melanoma Genomics: Shifting Focus from Inter- to Intrapatient Variation
Authors: A. Hunter Shain
Journal: Cancer Discovery (2023)

Summary: Traditionally, omic studies have prioritized the number of patients over the number of tumors per patient, but in a reversal of this study design, Spain and colleagues performed the largest intrapatient analysis of melanoma to date. Their work reveals mechanisms of treatment resistance, patterns of metastatic dissemination, and new insights into the evolutionary trajectories of melanoma. See related article by Spain et al., p. 1364 (1).
Immunochemotherapy for life-threatening haematological malignancies in pregnancy: a systematic review of the literature and cross-sectional analysis of clinical trial eligibility
Authors: Georgia S Mills, Verity Chadwick, Catherine Tang, Jacinta Perram, Mary Ann Anderson, Antoinette Anazodo, Giselle Kidson-Gerber, Antonia Shand, Orly Lavee, Barbara Withers, Sam Milliken, Pietro R Di Ciaccio, Nada Hamad
Journal: The Lancet Haematology (2023)